The compounds of interest, and their related syntheses appeared in the literature starting in 1976. However, due to the low overall yield obtained in their preparation, a great deal of improvement was desired. A synthetic route leading to analgesics of the above-cited type is described in the literature, see Synthetic Analgesics, Arzeim-Forsch. 26, 1548 (1976) and U.S. Pat. No. 4,179,569, Dec. 18, 1979. This synthesis is shown below: ##STR1##
It should be noted that when R is a phenylethyl group, the product is called Carfentanil, one of the most biologically active in this series.
The reaction of 1-phenylethyl-4-piperidine (1) with KCN and aniline in acetic acid gives 4-anilino-4-cyano-1-(2-phenylethyl)piperidine (2), which is hydrolyzed with cool H.sub.2 SO.sub.4 to the corresponding amide (3). This compound is hydrolyzed further with KOH in refluxing ethylene glycol affording the free acid (4), which is methylated with methanol and an acid catalyst to the methyl ester (5). Finally this compound is acylated with propionic anhydride at reflux temperature to give the analgesic compound (6).
For several N-alkyl or alkaryl groups of interest, the route described in the series of formulas gives satisfactory results. When R is phenylethyl, however, in order to prepare Carfentanil, the yield of the hydrolysis of the nitrile to the corresponding amide (Equation B) is very low (about 7% or less). The predominant reaction is the reverse of Equation A, and the main product is the ketone (1) again.